The key component of a pMDI is a canister which contains a liquid phase such as a propellant (which may also include low volatility co-solvents) in which the active pharmaceutical ingredient (API) is present either in solution or suspended in the form of micronised particles (either micrometers or nanometers in diameter). The propellants commonly used are hydrofluoroalkanes (HFA) such as HFA 134a (tetrafluorethane) and HFA 227ea (heptafluoropropane). Solvents of relatively low volatility e.g. ethanol, and/or formulation modifiers e.g. glycerol are often included in the formulations to enhance API solubility in the propellant to yield a solution formulation, or to modify the aerosol properties of the formulation (1, 2). Many APIs or drugs however do not have sufficient solubility in HFA/solvent blends or, alternatively, are not chemically stable in solution and as a result suspension systems must be formulated. Low volatility solvents are also used in suspension systems to promote the solubility of surfactants which function to stabilize the suspension of micronised API particles. pMDIs are the most commonly used delivery systems for treating asthma, chronic obstructive pulmonary disease (COPD) and other diseases of the respiratory tract and for administering to the buccal cavity.
The pMDI container (usually in the form of an aluminium canister which may be anodized or coated, or a stainless steel canister) provides a reservoir for doses, typically between 60 to 200 metered doses, which will usually provide one months' medication for a patient, or may provide one dose of a rescue medication. The doses are dispensed via a metering valve which is crimped onto the pMDI container. Typical metered volumes range from 25-75 μL. In use, the canister is housed in a plastic actuator which enables the metered volume to be delivered as an aerosol to the patient via the actuator mouthpiece.
Manufacturing processes fall broadly into two categories; single stage filling or two-stage filling. In the former process the formulation consists of an API, or combination of APIs, either suspended or dissolved in the propellant (which may also contain a small fraction of low volatility solvent e.g. ethanol and an appropriate surfactant). During manufacture the propellant is maintained as a liquid by the use of high pressure or low temperature. In the case of a suspension formulation the micronised API (ideal particle size in the region of 3 μm) must be homogenously dispersed during all stages of manufacture and care is taken to ensure that the particulate API does not settle or aggregate in any of the vessels, homogenisers, pumps, machinery or filling lines required to dispense the formulation into the pMDI container. Very often it is necessary to continuously homogenise and recirculate the liquefied suspension formulation to ensure uniform dispersion of the API. During filling care must be taken to ensure accurate and reproducible filling of API/propellant into the pMDI container. Filling may be performed into open canisters followed by crimping on of the metering valve (cold filling) or alternatively the API/propellant may be dispensed into the sealed cans via the metering valve (pressure filling).
For two-stage filling, the “first stage” typically involves dispensing of a concentrated suspension or solution of API in a low volatility solvent or suspending medium e.g. ethanol (with or without appropriate surfactant) into an open pMDI container followed by crimping on of the metering valve. Care must be taken to ensure that the filling procedure delivers an accurate and reproducible amount of API solution or suspension into every container and very often it is necessary to continuously homogenise and recirculate formulations to ensure uniform dispersion of the API. The “second stage” involves the addition of an accurate and reproducible amount of propellant.
One of the inventors has previously shown (3) that effective formulations for suspension pMDIs may include a (second) particulate material (excipient) in addition to the micronised API within the liquid propellant. The particle size distribution of the second particulate is predominantly greater than that of the micronised API. The particulate carrier and the API may be present as either a simple admixture or with some or all of the smaller API particles interacting with the larger particles of the second particulate material.
However, in contrast to this earlier work it is herein disclosed a new pMDI formulation and a process for the manufacturing of a pMDI, wherein the API is added to a canister in tablet form prior to the processes of (in the order consistent with pressure or low temperature filling) crimping the metering valve on the canister and filling with propellant.
There is therefore disclosed herein the production of a pMDI using at least one API(s) in the form of a tablet wherein the API is either on its own or with at least one excipient.